A genetic linkage study of breast cancer is underway on four well- defined clinico-genetic disorders, each of which involves breast cancer as an integral component. These include the Torre-Muir syndrome, Li-Fraumeni syndrome, familial breast-ovarian cancer, and familial site-specific breast cancer. Because of their association with breast cancer, their being examples of dominantly inherited conditions, their relatively early ages at onset and involving identifying lesions and tumors, these entitites offer a unique opportunity for investigating the genetics of breast cancer. We are presently utilizing these disorders to localize the genetic loci influencing breast cancer to specific chromosomes, and thereby determine whether the genes for these disorders are the same or belong to different loci on the same or different chromosomes. To date, 55 pedigrees have been ascertained, updated, and evaluated, and over 800 blood samples from members of these pedigrees have been typed for genetic markers. Linkage analysis of the breast-ovarian and Li-Fraumeni syndrome pedigrees has been largely completed and analyses have begun on the site-specific and Torre-Muir pedigrees. The result to date suggest that the gene influencing susceptiblity to breast-ovarian cancer is on the short are of chromsome 1 in close proximity to the RH blood group locus which maps to 1p34-36. Close linkage to the Rh locus can be excluded for the Li-Fraumeni and Torre- Muir syndromes. We propose to complete the evaluation of each entity for evdience of linkage with increased emphasis on the use of DNA markers to cover more completely the human gene map, and to investigate more intensively the linkage in the breast- ovarian cancer pedigrees by employing DNA polymorphisms mapping to the 1p34-36 region. This project should provide insight into the genetics of breast cancer and the organization of the human genome; evidence of close linkage would also provide a means by which high risk individuals could be identified through a linked marker prior to the onset of tumors.